The Interleukin-8 (IL-8/CXCL8) Receptor Inhibitor Reparixin Improves Neurological Deficits and Reduces Long-term Inflammation in Permanent and Transient Cerebral Ischemia in Rats

Abstract

Leukocyte infiltration is viewed as a pharmacological target in cerebral ischemia. We previously reported that reparixin, a CXCL8 receptor blocker that inhibits neutrophil infiltration, and related molecules can reduce infarct size in a rat model of transient middle cerebral artery occlusion (MCAO). The study aims were to compare the effects of reparixin in transient and permanent MCAO using varied treatment schedules and therapeutic windows to evaluate effects on long-term neurological deficits and late inflammatory response. Reparixin, administered for 1 to 3 days, 3.5 to 6 h after MCAO, ameliorates neurological function recovery and inhibits long-term inflammation. The infarct size reduction at 24 h, evaluated by TTC staining, is more pronounced in transient MCAO. MRI analysis identified a decrease in the progression of infarct size by reparixin that was more evident at 48 h in permanent MCAO, and was associated with a significantly improved recovery from long-term neurological deficits.

Endothelin-1 induced MCAO: Dose dependency of cerebral blood flow

“…Several model-specific complications have also been reported: non-adequate or insufficient occlusion (Laing et al, 1993), intraluminal thrombus formation (Koizumi et al, 1986;Muller et al, 1994;Rabb, 1996), subarachnoid hemorrhage (Longa et al, 1989;Laing et al, 1993), and hyperthermia (Memezawa et al, 1995). Despite these complications, the filament model is frequently used and suitable for drug related studies (Villa et al, 2007;Lyden et al, 2000;Nagel et al, 2007;Qiu et al, 2006;Zhao et al, 2006;Lumenta et al, 2006). A current ongoing study in our lab involves the administration of erythropoietin in aged rats in conjunction with the filament MCAO model.…”

Chemokines in CNS injury and repair

“…A CXCL8-neutralizing antibody is able to reduce brain oedema and cerebral infarct size (Matsumoto et al 1997). Inhibition of CXCL8 receptor by reparixin causes the same beneficial effect in rats suffering from permanent and transient cerebral ischaemia resulting in the attenuation of neurological deficits (Villa et al 2007). In the clamp SCI, the therapeutic steroid analogue lazaroid U-74389 G, which inhibits lipid peroxidation but does not have the side effects of steroid therapy (Kavanagh and Kam 2001), has been shown to reduce the production of systemic and spinal CXCL8 (Kunihara et al 2000).…”

Small Molecule Antagonists of Chemokine Receptors - is Promiscuity a Virtue?

“…Notably, CXCL8 is still able to fully activate mutant forms of the receptor which are insensitive to reparixin, suggesting that reparixin is an allosteric modulator of CXCR1 and CXCR2, with agonist and antagonist binding to distinct sites within the receptors. Reparixin has proven to be both efficacious and well-tolerated in a variety of rodent models of ischemia/reperfusion injury [40,41]. However, reports of a recent clinical trial to determine the efficacy of reparixin in preventing primary graft dysfunction following lung transplantation found no differences in primary efficacy endpoint (PaO 2 /FiO 2 ratios immediately and 24 hours after transplantation) between groups taking placebo and those taking reparixin [42].…”